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Viper snakes can kill, but a protein in their venom prevents the spread of tumors in laboratory mice, and a molecular 'portrait' now under development may explain why, according to a University of Delaware scientist profiled in the new issue of Cardiology Today.

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Viper snakes can kill, but a protein in their venom prevents the spread oftumors in laboratory mice, and a molecular 'portrait' now under development mayexplain why, according to a University of Delaware scientist profiled in the newissue of Cardiology Today, mailed Feb. 4.

"The next step," McLane says, "is to find out exactly what it is about thestructure of eristostatin that gives it this exciting capability in mice." WithUD colleague Mary E. Miele, an assistant professor of medical technology, McLanealso plans to study eristostatin's effect on metastatic melanoma cells.

Eristostatin is one of many viper-venom "disintegrins"--proteins that interactwith a family of cellular receptors called integrins, McLane explains.Disintegrins are "potent inhibitors of platelet aggregation and cell adhesion,"and therefore prevent an early step in blood clotting, Niewiarowski says. Onceinjected into a victim's bloodstream, disintegrins from viper-snake venom stopthe sticky protein, fibrinogen, from binding with platelets. The global quest tobetter understand disintegrins, launched in the late 1980s, already has resultedin a commercially available anti-platelet drug, based on a synthetic version ofthese proteins' "three-dimensional scaffolding," McLane notes.

McLane and Niewiarowski got their first glimpse of eristostatin's anti-tumoraction several years ago, as part of a project directed by Canadian researcherVincent L. Morris of the University of Western Ontario. Melanoma cells wereinjected into cancer-susceptible mice, some of which also received eristostatin.Eleven days later, eristostatin had clearly reduced the average number of livertumors--from 14.4 among unprotected mice to 0.6 within the treated population,the researchers reported in Experimental Cell Research (Vol. 219, pp. 571-578,1995).

Since then, McLane's ongoing molecular biology studies of eristostatin havefocused on a protruding section of amino acids--the RGD loop, composed ofarginine, glycine and aspartic acid--which is known to play a key role inbinding with integrins. To learn more about the RGD loop, McLane compareseristostatin with echistatin, a disintegrin from the venom of Echis carinatus,another viper-type snake from the Middle East.

Though the amino-acid sequences of the two proteins are 68 percent identical,McLane says, echistatin exhibits markedly different binding behaviors. Comparedto eristostatin, for instance, echistatin is far less effective at preventingfibrinogen from interacting with integrins, and can't prevent melanoma cellmetastasis. Echistatin also interacts with receptors on blood vessel walls--atrick that eristostatin has not mastered. "We want to learn what structuraldifferences allow echistatin to be promiscuous, binding to so many receptors,while eristostatin is so selective," McLane explains.

How does she compare the two proteins? First, she manipulates a gene containingthe code for echistatin to create mutations within echistatin's RGD loop. Next,she places the resulting DNA (deoxyribonucleic acid) in a bacterial expressionsystem, thereby forcing the bacteria to make the altered snake protein. Thegoal, she says, is to give echistatin the binding region of eristostatin--oneamino acid at a time. Finally, she tests each mutant's ability to interact withreceptors on platelets, to identify the exact sequences most critical forbinding. She soon will conduct the same tests using lymphocytes, ordisease-fighting cells. And, with Miele, she will focus on whether eristostatincan stop cancer cell growth.

McLane's work, funded by the American Heart Association (AHA), thus far suggeststhat a triple mutation in echistatin can make it act like eristostatin withplatelets and endothelial cells. In other words, she says, "Out of 13 aminoacids in echistatin's RGD loop, I can change three and make it work likeeristostatin." Although she suspects that eristostatin's ability to stop thespread of tumors in mice may be mediated by an integrin receptor, which cancercells have in common with white blood cells, the exact mechanisms remain amystery--for now. "This question has been eluding us, but I now have the genethat codes for eristostatin, and I'm optimistic that I will discover someanswers." With AHA support, meanwhile, McLane also explores the potential ofdisintegrins for treating thrombosis--especially arterial thrombosis.

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The above story is based on materials provided by University Of Delaware. Note: Materials may be edited for content and length.

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